Despite considerable recent progress, an immunization strategy that is capable of inducing immune responses that can prevent or control HIV infection has not yet been achieved. By significantly reducing viral lode and inducing T-cell recovery, treatment of HIV infected individuals with high active anti-retroviral therapy (HAART) regimens may provide an opportunity for HIV-specific immunization. In this setting of recovery of T-lymphocyte function, HIV-specific immunizations may be effective. DNA-based immunization strategies can elicit both humoral and CTL-mediated antigen-specific immune responses and have significant potential for the treatment and prevention of HIV infection. The mechanisms by which genetic immunization induce immunity are unclear. The goal of this project is to elucidate key features of the mechanisms of DNA-based immunization, and to use this information for the rationale development of DNA-based immunization strategies against HIV. To accomplish this we will utilize murine and primate models to determine the role of professional antigen presenting cells in the initiation of the immune response induced by different methods of DNA-based immunizations. We will correlate variables effecting antigen expression and presentation with in vivo immunogenicity. Based on this analysis, the most effective immunization strategies will be evaluated as adjuvant immunotherapies to HAART regimens using an SIV infected simian model. These studies contribute to the overall Program by developing and directly comparing DNA-based immunization strategies as an alternative to dendritic cell adoptive transfer immunotherapies. These studies are designed to demonstrate feasibility and provide rationale for continuing development of DNA-based immunization as adjuvant therapy for HIV disease, including the initiation of human clinical trials.